Influence of SARS-CoV-2 infection before and during organogenesis on embryo implantation and development outcomes: A prospective cohort observational study.

Abstract

Background: Extensive research has demonstrated the detrimental effects of COVID-19 on maternal-fetal outcomes. However, few studies have examined the impact of SARS-CoV-2 infection before and during organogenesis on human embryo implantation and subsequent development. Additionally, the influence of SARS-CoV-2 on the endometrial microenvironment, which is critical for embryo implantation, remains poorly understood. This study seeks to address these gaps in knowledge.

Methods and findings: We prospectively enrolled 971 participants undergoing frozen-thawed embryo transfer (FET) during the final two months of 2022, coinciding with the nationwide COVID19 outbreak following the end of China's Zero-Covid policy. Patients undergoing FET during this period were at high risk of SARS-CoV-2 infection before and during organogenesis. Based on self-reported symptoms and nucleic acid testing, 520 individuals were confirmed to have SARS-CoV-2 infection, while 451 were uninfected. Consistent with existing literature, our study reinforced that SARS-CoV-2 infection negatively impacted pregnancy outcomes, as evidenced by reduced clinical pregnancy (52.69% vs. 76.50%, RR = 60.506, [95%CI, 0.259 ~ 0.452]) and live birth rates (46.54% vs. 60.09%, RR = 17.865, [95%CI, 0.448 ~ 0.746]), alongside an increase in obstetric complications (35.89% vs. 27.37%, RR = 4.380, [95%CI, 1.055 ~ 2.223]). Seven fetal congenital heart defects (CHDs) were observed in the infected group versus one in uninfected population. Bioinformatic analysis of endometrial mRNA profiles showed SARS-CoV-2 infection significantly downregulated key endometrial receptivity molecules, increased natural killer cell and mast cell infiltration, and disrupted the balance of cytokine and chemokine. Moreover, our findings demonstrated that SARS-CoV-2 infection downregulated the transcriptional activity of endometrial SLC6A, a serotonin transporter, and ErbB-2, a mediator of serotonin-regulated differentiation in cardiac development. This disruption in serotonin signaling may underlie the pathogenesis of congenital heart disease.

Conclusions: SARS-CoV-2 infection before and during organogenesis negatively impacts embryo implantation and development, primarily through mechanisms involving compromised endometrial receptivity and disruption of the local immune microenvironment.